WO2010017150A1 - Composés utiles comme inhibiteurs de protéine kinases - Google Patents

Composés utiles comme inhibiteurs de protéine kinases Download PDF

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WO2010017150A1
WO2010017150A1 PCT/US2009/052617 US2009052617W WO2010017150A1 WO 2010017150 A1 WO2010017150 A1 WO 2010017150A1 US 2009052617 W US2009052617 W US 2009052617W WO 2010017150 A1 WO2010017150 A1 WO 2010017150A1
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pyrrolo
carboxamide
dihydropyridine
pyridin
alkylene
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PCT/US2009/052617
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Anil Vasudevan
Brian S. Brown
Ryan G. Keddy
Adrian D. Hobson
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Abbott Laboratories
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Priority to MX2011001370A priority Critical patent/MX2011001370A/es
Priority to CN2009801395015A priority patent/CN102170883A/zh
Priority to JP2011522150A priority patent/JP2011530518A/ja
Priority to CA2731095A priority patent/CA2731095A1/fr
Priority to EP09805407A priority patent/EP2323659A4/fr
Publication of WO2010017150A1 publication Critical patent/WO2010017150A1/fr

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Definitions

  • Bicyclic compounds that are inhibitors of Rho kinases (ROCK), compositions including such compounds, and methods for treating conditions and disorders using such compounds and compositions are provided.
  • ROCK Rho kinases
  • Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the y- phosphate of the ATP-Mg 2+ complex to the amino acid side chain.
  • protein kinases Due to their physiological relevance, variety and ubiquitousness, protein kinases have become one of the most important and widely studied families of enzymes in biochemical and medical research.
  • the protein kinase family of enzymes is typically classified into two main subfamilies: Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the amino acid residue they phosphorylate.
  • the serine/threonine kinases includes cyclic AMP-and cyclic GMP-dependent protein kinases, calcium- and phospholipid-dependent protein kinase, calcium-and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases.
  • tyrosine kinases phosphorylate tyrosine residues.
  • Tyrosine kinases play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet derived growth factor receptor and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much work is also in progress to identify modulators of tyrosine kinases as well.
  • RhoA-signalling pathway A major signal transduction system utilized by cells is the RhoA-signalling pathway.
  • RhoA is a small GTP binding protein that can be activated by several extracellular stimuli such as growth factor, hormones, mechanic stress, or osmotic change as well as high concentration of metabolite like glucose.
  • RhoA activation involves GTP binding, conformation alteration, post-translational modification (geranylization and farnesylation) and activation of its intrinsic GTPase activity.
  • Activated RhoA is capable of interacting with several effector proteins including ROCKs (Rho kinase) and transmit signals into cellular cytoplasm and nucleus.
  • Rho kinase is found in two iso forms encoded by two different genes of ROCK, ROCK 1 (also known as ROCK ⁇ or pi 60- ROCK) and ROCK 2 (also known as ROCK ⁇ ). Both ROCK 1 and ROCK 2 contain an amino-terminal catalytic kinase domain, a central coiled-coil domain of about 600 amino acids, and a carboxyl-terminal pleckstrin homology (PH) domain that is split by a cysteine-rich region. Rho/GTP interacts with the C-terminal portion of the central coiled-coil domain and activates the kinase activity of ROCK.
  • ROCK 1 also known as ROCK ⁇ or pi 60- ROCK
  • ROCK 2 also known as ROCK ⁇
  • Both ROCK 1 and ROCK 2 contain an amino-terminal catalytic kinase domain, a central coiled-coil domain of about 600 amino acids, and a carboxyl-terminal pleckstrin homology (PH) domain
  • ROCKl and 2 constitute a family of serine/threonine kinases that can be activated by RhoA-GTP complex via physical association.
  • Activated ROCKs phosphorylate a number of substrates and play important roles in pivotal cellular functions.
  • the substrates for ROCKs include myosin binding subunit of myosin light chain phosphatase (MBS, also named MYPTl), adducin, moesin, myosin light chain (MLC), LIM kinase as well as transcription factor FHL.
  • MCS myosin binding subunit of myosin light chain phosphatase
  • MLC myosin light chain
  • LIM kinase as well as transcription factor FHL.
  • the phosphorylation of theses substrates modulate the biological activity of the proteins and thus provide a means to alter cell's response to external stimuli.
  • One well documented example is the participation of ROCK in smooth muscle contraction.
  • RhoA kinase activity of ROCKl and which in turn phosphorylates MBS.
  • MLCK calcium-dependent myosin light chain kinase
  • ROCKs have also been shown to be involved in cellular functions including apoptosis, cell migration, transcriptional activation, fibrosis, cytokinesis, inflammation and cell proliferation.
  • ROCK plays a critical role in the inhibition of axonal growth by myelin-associated inhibitory factors such as myelin-associated glycoprotein (MAG).
  • MAG myelin-associated glycoprotein
  • ROCK-activity also mediates the collapse of growth cones in developing neurons. Both processes are thought to be mediated by ROCK-induced phosphorylation of substrates such as LIM kinase and myosin light chain phosphatase, resulting in increased contractility of the neuronal actin-myosin system.
  • Rho/ROCK pathway Abnormal activation of the Rho/ROCK pathway has been observed in various disorders (Wettschureck, N., Offermanns, S., Rho/Rho-kinase mediated signaling in physiology and pathophysiology. J. MoI. Med. 80, 2002, 629-638; M ⁇ ller, B.K., Mack, H., Teusch, N., Rho kinase, a promising drug target for neurological disorders. Nat. Drug Discov. Rev. 4, 2005, 387-398; Hu, E, Lee, D., ROCK inhibitors as potential therapeutic agents for cardiovascular diseases. Curr. Opin. Investig. Drugs. 4, 2003, 1065-1075).
  • ROCKs phosphorylate the myosin binding subunit of myosin light chain (MLC) phosphatase (MLCP), resulting in increased myosin phosphorylation and actin-myosin contraction (Somlyo, A.P., Somlyo, A.V., Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol. Rev.83, 2003, 1325-1358).
  • MLC myosin light chain
  • cardiovascular diseases such as hypertension (Satoh S., Rreutz R., WiIm C, Ganten D., Pfitzer G., Augmented agonist-induced Ca 2+ - sensitization of coronary artery contraction in genetically hypertensive rats.
  • cardiovascular diseases such as hypertension (Satoh S., Rreutz R., WiIm C, Ganten D., Pfitzer G., Augmented agonist-induced Ca 2+ - sensitization of coronary artery contraction in genetically hypertensive rats.
  • cardiac hypertrophy Hoshijima, M., Sah, V. P., Wang, Y., Chien, K.R., Brown, J.H.
  • Rho is required for Galphaq and alpha 1 -adrenergic receptor signal- 637 ing in cardiomyocytes. Dissociation of Ras and Rho pathways.
  • Rho/ROCK activity Further diseases related to abnormal Rho/ROCK activity are cancer (Aznar, S., Fernandez -Valeron, P., Espina, C, Lacal, J. C, and Rho GTPases: potential candidates for anticancer therapy. Cancer Lett. 206, 2004, 181-191; Yin, L. et al, Fasudil inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo.
  • Inhibitors of ROCKs have been suggested for use in the treatments of a variety of diseases. They include cardiovascular diseases such as hypertension, chronic and congestive heart failure, and cardiac hypertrophy, chronic renal failure, furthermore cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension, and ocular hypertension. In addition, because of their muscle relaxing properties, they are also suitable for asthma, male erectile dysfunctions, female sexual dysfunction and over-active bladder syndrome, and preterm labor. Several recent studies have reported the beneficial effects of ROCK inhibitors in ischemia-reperfusion and myocardial infarction.
  • ROCK inhibitors Y- 27632 and fasudil were shown to decrease ischemia-reperfusion injury, myocardial infarct size, and myocardial fibrosis in response to experimental myocardial infarction (MI) and in a rat model of chronic hypertension induced congestive heart failure (Masumoto, A., Mohri, M., Shimokaw,a H., Urakami, L., Usui, M., Takeshita, A., Suppression of coronary artery spasm by the rho-kinase inhibitor fasudil in patients with vasospastic angina.
  • MI myocardial infarction
  • Circulation 104 [Suppl II], 2001, II691; Morishige K, Shimokawa H, Eto Y, Kandabashi T, Miyata K, Matsumoto Y, Hoshijima M, Kaibuchi K, Takeshita A, Adenovirus-mediated transfer of dominant-negative rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo.
  • ROCKs can interact with other signalling pathways resulting in inhibition of phosphoinositide- 3 kinase (PI-3K), endothelial nitric oxide synthase (eNOS) pathways, and activation of plasminogen activator inhibitor- 1 (PAI-I) which can contribute to endothelial dysfunction like restenosis and atherosclerosis.
  • PI-3K phosphoinositide- 3 kinase
  • eNOS endothelial nitric oxide synthase
  • PAI-I plasminogen activator inhibitor- 1
  • ROCK inhibitors have been suggested for the treatment of restenosis and atherosclerosis (Iwasaki, H. et al., High glucose induces plasminogen activator inhibitor- 1 expression through Rho/Rho-kinase- mediated NF-kappaB activation in bovine aortic endothelial cells. Atherosclerosis, 2007, Jan 31).
  • vascular intimal thickening in vein grafts after surgery is the major cause of late graft failure.
  • ROCK inhibitor fasudil the intimal thickening and vascular smooth muscle cell (VSMC) proliferation was significantly suppressed, whereas VSMC apoptosis was enhanced in the weeks following the procedure, suggesting that ROCK inhibitors can be used as a therapeutic agent for the prevention of graft failure.
  • Cytoplasmic p21 (C ipl /WAFl) enhances axonal regeneration and functional recovery after spinal cord injury in rats. Neuroscience 127, 2004, 155-164). ROCK inhibitors are therefore likely to be useful for regenerative (recovery) treatment of CNS disorders such as spinal cord injury, acute neuronal injury (stroke, traumatic brain injury) (Okamura N et al., Vasodilator effects of fasudil, a Rho-kinase inhibitor, on retinal arterioles in stroke-prone spontaneously hypertensive rats. J Ocul Pharmacol Ther.
  • ROCK inhibitors are expected to be useful are Huntington's disease (Shao J, Welch WJ, Diprospero NA, Diamond MI. Phosphorylation of prof ⁇ lin by ROCKl regulates polyglutamine aggregation. MoI Cell Biol. 2008 Sep; 28(17):5196-208; Shao J, Welch WJ, Diamond MI. ROCK and PRK-2 mediate the inhibitory effect of Y-27632 on polyglutamine aggregation. FEBS Lett. 2008 May 28; 582(12): 1637- 42), spinal muscular atrophy (Bowerman M, Shafey D, Kothary R.
  • Rho A/ROCK pathway Smn depletion alters prof ⁇ lin II expression and leads to up regulation of the Rho A/ROCK pathway and defects in neuronal integrity. J MoI Neurosci. 2007; 32(2): 120-31) and amyotrophic lateral sclerosis. Inhibition of the Rho/ROCK pathway has also proved to be efficacious in other animal models of neurodegeneration like stroke and in inflammatory and demyelinating diseases like multiple sclerosis (Sun X et al., The selective Rho-kinase inhibitor Fasudil is protective and therapeutic in experimental autoimmune encephalomyelitis. J Neuroimmunol. 180, 2006, 126-34), acute and chronic pain (Inoue, M.
  • ROCK inhibitors have been shown to possess anti-inflammatory properties by decreased cytokine release, e.g.TNF ⁇ . Thus they can be used as treatment for neuroinflammatory diseases such as stroke, multiple sclerosis, Alzheimer's disease,
  • Parkinson's disease amyotrophic lateral sclerosis and inflammatory pain, as well as other inflammatory diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, asthma, irritable bowel syndrome, or inflammatory bowel disease (Segain J.P., Rho kinase blockade prevents inflammation via nuclear factor kappa B inhibition: evidence in Crohn's disease and experimental colitis. Gastroenterology. 124(5), 2003, 1180-7).
  • inhibition of ROCK results in disruption of inflammatory cell chemotaxis as well as inhibition of smooth muscle contraction in models of pulmonary inflammation associated with asthma.
  • Rho/ROCK pathway should be useful for the treatment of asthma (Kawaguchi A, Ohmori M, Harada K, Tsuruoka S, Sugimoto K, Fujimura A., The effect of a Rho kinase inhibitor Y- 27632 on superoxide production, aggregation and adhesion inhuman polymorphonuclear leukocytes. Eur J Pharmacol 403, 2000, 203-208 ; Lou Z, Billadeau DD, Savoy DN, Schoon RA, Leibson P.J., A role for a RhoA/ROCK/LIM-kinase pathway in the regulation of cytotoxic lymphocytes.
  • Rho-pl60 Rho coiled-coil kinase axis in the chemokine stromal cell-derived factor- 1 alpha-induced lymphocyte actomyosinand microtubular organization and chemotaxis.
  • ROCK inhibitors reduce cell proliferation and cell migration, they could be useful in treating cancer and tumor metastasis. ROCK inhibitors can also be beneficial in diseases with impaired blood brain barrier function, e.g. HIV-I encephalitis (Persidski Y et al., Rho-mediated regulation of tight junctions during monocyte migration across the blood- brain barrier in HIV-I encephalitis (HIVE). Blood. 107, 2006, 4770-4780) and Alzheimer's disease (Man S-M et al., Peripheral T cells over express MIP-Ia to enhance its transendothelial migration in Alzheimer's disease. Neurobiol. Of Aging 28, 2007, 485-496).
  • HIV-I encephalitis Persidski Y et al., Rho-mediated regulation of tight junctions during monocyte migration across the blood- brain barrier in HIV-I encephalitis (HIVE). Blood. 107, 2006, 4770-4780
  • Alzheimer's disease Man S-M et al., Perip
  • ROCK inhibitors suppress cytoskeletal rearrangement upon virus invasion, thus they also have potential therapeutic value in antiviral and anti-bacterial applications (Favoreel HW, Cytoskeletal rearrangements and cell extensions induced by the US3 kinase of an alphaherpesvirus are associated with enhanced spread. Proc Natl Acad Sci U S A. 102(25), 2006, 8990-5).
  • ROCKs have been reported to interfere with insulin signalling through serine phosphorylation of insulin receptor substrate- 1 (IRS-I), in cultured VSMC. Activation of RhoA/ROCK was observed in skeletal muscles and aortic tissues of Zucker obese rats. Inhibition of ROCK, by fasudil for 4 weeks, reduced blood pressure, corrected glucose and lipid metabolism, improved insulin signalling and endothelial dysfunction. In another experiment administration of high dose fasudil completely suppressed the development of diabetes, obesity, and dyslipidemia and increased serum adiponectin levels in OLETF rats.
  • ROCK inhibitors can therefore be useful for the treatment of insulin resistance and diabetes (Nakamura Y et al., Marked increase of insulin gene transcription by suppression of the Rho/Rho-kinase pathway. Biochem Biophys Res Commun. 350(1), 2006, 68-73; 66 Kikuchi Y et al., A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats. J Endocrinol.
  • ROCK inhibitor Fasudil increased cerebral blood flow and was neuroprotective under CNS ischemic conditions. ROCK inhibitors are expected to be useful for the treatment of ischemic CNS disorders and can therefore improve functional outcome in patients suffering from stroke, vascular or AD type dementia.
  • ROCK inhibitors Due to the efficacy of Y-27632 and fasudil in animal models of epileptogenesis, ROCK inhibitors have been suggested for the use in the treatments of epilepsy and seizure disorders (Inan SY, B ⁇ yukafsar K. Antiepileptic effects of two Rho-kinase inhibitors, Y- 27632 and fasudil, in mice. Br. J. Pharmacol, advance online publication, 9 June 2008; doi:10.1038/bjp.2008.225)
  • ROCK inhibitors are also expected to be useful for the treatment of glaucoma, psoriasis, retinopathy and benign prostatic hypertrophy.
  • ROCK inhibitors suppress cytoskeletal rearrangement upon virus invasion, thus they also have potential therapeutic value in antiviral and anti-bacterial applications.
  • ROCKs have been implicated in neuronal morphogenesis, connectivity, and plasticity in general, they are expected to be useful for the treatment of psychiatric disorders, e.g. depression, schizophrenia, obsessive compulsive disorder and bipolar disorders.
  • ROCK inhibitors have been described in e.g. WO 2007/026920, WO 2005/074643, and WO 2004/016597. However, their affinity and selectivity or their pharmacological profile is not yet satisfactory.
  • bicyclic compounds that are Rho kinases inhibitors, pharmaceutical compositions including such compounds, and methods for the treatment of disorders using these compounds and pharmaceutical compositions.
  • the present invention is directed towards compounds of formula (I), or pharmaceutically acceptable salts, solvates, prodrugs, salts of prodrugs, or combinations thereof,
  • R 1 represents optional substituent(s) on ring B, and each occurrence of R 1 is independently alkyl, CN, -O(R la ), -N(R lb )(R lc ), -(C L6 alkylenyl)-O(R la ), -(C L6 alkylene)-N(R lb )(R lc ), -(C L6 alkylene)-CN, alkenyl, halogen, or haloalkyl;
  • R la and R lb are each independently hydrogen, alkyl or haloalkyl
  • R lc at each occurrence, is independently hydrogen, alkyl, haloalkyl, O(R za ), C(O)NR za R zb , C(O)R zb , S(O) 2 R ZC , or S(O) 2 NR za R zb
  • R 2 represents optional substituent(s) on the carbon atom(s) of ring A, and each occurrence of R 2 is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycle, arylalkyl, heteroarylalkyl, cycloalkylalkyl, cycloalkenylalkyl, or heterocycleal
  • R 3 represents optional substituent(s) on the carbon atom(s) of ring A; m is 0, 1, 2, or 3; n is 0 or 1 ; p is 0, 1, 2, or 3;
  • A is formula (i), (ii), or (iii)
  • R 2 and R 3 are optional susbtituents on any substitutable carbon atoms within the bicyclic ring;
  • X 2 is hydroxyalkyl, -alkenylene-G 1 , -(CR 6a R 6b ) r -X 3 -G ⁇ -(CR 6a R 6b ) q -X 3 -(CR 6a R 6b ) q -G 1 , or J A wherein X 3 is O, S, N(H), or N(alkyl);
  • G 1 at each occurrence, is independently cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, or aryl, each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by R 7b ;
  • J A is a monocyclic heterocycle or a monocyclic cycloalkyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents as represented by R 7JA ;
  • two R 7JA on the adjacent carbon atoms of J A together with the carbon atoms to which they are attached, optionally form a benzo, a monocyclic heterocycle, a monocyclic cycloalkyl, or a monocyclic cycloalkenyl ring wherein each of the rings is independently unsubstituted or substituted with 1, 2, or 3 substituents as represented by R 7b ;
  • R 6a and R 6b can be the same or different, and at each occurrence, are each independently hydrogen, halogen, haloalkyl, aryl, -OR U , -N(R V )(R W ), or alkyl; wherein the alkyl is optionally substituted with one substituent selected from the group consisting of - OR U , -N(R V )(R W ), aryl, and monocyclic heterocycle; wherein the aryl group and the monocyclic heterocycle group are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by R 6za ; or X 1 -X 2 together is a five membered monocyclic heterocycle or a five membered monocyclic heteroaryl ring, optionally substituted with 1, 2, 3, or 4 substituents as represented by R 7c ;
  • R 4 is hydrogen or alkyl which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of OH, O(alkyl), halogen, -C(O)(alkyl), -C(O)O(alkyl), -C(O)NH 2 , -C(O)N(H)(alkyl), -C(O)N(alkyl) 2 , cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl;
  • R u , R v , and R w are each independently hydrogen, alkyl, or haloalkyl;
  • R 7J and R 7c are each independently alkyl, alkenyl, alkynyl, halogen, oxo, NO 2 , CN, haloalkyl, OR a , OC(O)R a , NR a R b , N(R b )C(0)R a , N(R b )S(O) 2 R a , SR a , S(O)R C , S(O) 2 R C , S(O) 2 NR a R b , C(O)R a , C(O)OR a , C(0)NR a R b , -(d_ 6 alkylene)-NO 2 , -(d_ 6 alkylene)-CN, -(CL 6 alkylene)-OR a , C(0)NR a R b ,
  • R 7b is independently alkyl, alkenyl, alkynyl, halogen, oxo, NO 2 , CN, haloalkyl, OR 7ab , OC(O)R 7ab , NR 7ab R b , N(R b )C(0)R 7ab , N(R b )S(O) 2 R 7ab , SR 7ab , S(O)R C , S(O) 2 R C , S(O) 2 NR 7ab R b , C(O)R 7ab , C(O)OR 7ab , C(0)NR 7ab R b , -(d_ 6 alkylene)-NO 2 , -(d_ 6 alkylene)-CN, -(C 1-6 alkylene)-OR 7ab , -(C L6 alkylene)-OC(O)R 7ab , -(d_ 6 alkylene
  • G 2 is independently cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, or aryl, each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by R 7d ;
  • R 3 , R 7a , R 6za , and R 7d are each independently alkyl, alkenyl, alkynyl, halogen, NO 2 , CN, haloalkyl, OR a , OC(O)R a , NR a R b , N(R b )C(0)R a , N(R b )S(O) 2 R a , SR a , S(O)R C , S(O) 2 R C , S(O) 2 NR a R b , C(O)R a , C(O)OR a , C(0)NR a R b , -(C 1-6 alkylene)-NO 2 , -(CL 6 alkylene)-CN, -(d_ 6 alkylene)-OR a , -(d_ 6 alkylene)-OC(O)R a , -(d_ 6 alkylene)-
  • R a and R b are each independently hydrogen, alkyl, or haloalkyl;
  • R ax and R bx are each independently hydrogen, halogen, alkyl, or haloalkyl;
  • R 7ab is independently hydrogen, alkyl, haloalkyl, G 2 , or -(C L6 alkylene)-G 2 ;
  • R c at each occurrence, is independently alkyl or haloalkyl; q, at each occurrence, is independently 1, 2, 3, or 4; t is 1, 2, or 3; and r is 2, 3, or 4; with the proviso that
  • compositions including therapeutically effective amounts of one or more compounds presented herein, or pharmaceutically acceptable salts or solvates thereof, in combination with one or more pharmaceutically acceptable carrier, adjuvants, excipients, or other auxiliary substances. These pharmaceutical compositions are useful for treating diseases as described herein.
  • compositions of such compounds or pharmaceutically acceptable salts or solvates thereof are useful for the prevention or treatment of the diseases.
  • the compounds of the present invention have inhibitory activity against ROCK-I and ROCK-2 kinases and are thus useful for the inhibition of such kinases. Accordingly, the compounds or pharmaceutically acceptable salts or solvates thereof can be useful as active ingredients for the preparation of compositions, which enable preventive and/or therapeutic treatment of diseases or conditions caused by abnormal ROCK kinases (including ROCK-I and ROCK-2) activity.
  • the diseases which respond to the modulation of ROCKs, in particular to ROCKs inhibition include, but are not limited to, pain such as, but not limited to, neuropathtic pain, nociceptive pain, inflammatory pain, and cancer pain; cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, atherosclerosis, asthma, male erectile dysfunctions, female sexual dysfunction, over-active bladder syndrome, neuroinflammatory diseases such as stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and inflammatory pain, as well as other inflammatory diseases such as rheumatoid arthritis, irritable bowel syndrome, or inflammatory bowel disease.
  • pain such as, but not limited to, neuropathtic pain, nociceptive pain, inflammatory pain, and cancer pain
  • cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, atherosclerosis, asthma, male erectile dysfunctions, female
  • ROCK inhibitors can be used as drugs for neuronal regeneration, inducing new axonal growth and axonal rewiring across lesions within the CNS.
  • ROCK inhibitors are therefore useful for regenerative (recovery) treatment of CNS disorders such as spinal cord injury, acute neuronal injury (stroke, traumatic brain injury), Parkinson's disease, Alzheimer disease and other neurodegenerative disorders, such as, in particular, Huntington's disease, spinal muscular atrophy, and amyotrophic lateral sclerosis. Since ROCK inhibitors reduce cell proliferation and cell migration, they could be useful in treating cancer and tumor metastasis.
  • ROCK inhibitors suppress cytoskeletal rearrangement upon virus invasion and also have potential therapeutic value in anti-viral and anti- bacterial applications.
  • ROCK inhibitors can also be useful for the treatment of insulin resistance and diabetes.
  • ROCK inhibitors can furthermore be useful for the treatment of ischemic CNS disorders, vascular or AD type dementia, glaucoma, psoriasis, retinopathy, benign prostatic hypertrophy, psychiatric disorders, in particular depression, schizophrenia, obsessive compulsive disorder and bipolar disorder, epilepsy and seizure disorders, for decreasing ischemia-reperfusion injury, myocardial infarct size and myocardial fibrosis, and for the prevention of graft failure.
  • the compounds described herein can be used for treating the above-listed disorders. More preferably, they are used for treating pain, asthma, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and spinal cord injuries.
  • a further aspect provides methods of treating diseases as described herein above. The methods include administering to the subject (including human) in need thereof therapeutically effective amounts of one or more compounds described herein or pharmaceutically acceptable salts or solvates thereof, with or without one or more pharmaceutically acceptable carriers, excipients, adjuvants, or other auxiliary substances.
  • the present application further provides uses of compounds described herein or pharmaceutically acceptable salts or solvates thereof, with or without one or more pharmaceutically acceptable carriers, excipients, adjuvants, or other auxiliary substances, in the manufacture of medicaments for the treatment of the diseases or conditions described herein.
  • compositions including such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.
  • one or more variable can occur more than one time in any substituent or in the compounds described or any other formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents or variables are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a reaction mixture. a. Definitions As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, for example, 2-6 carbons, and more preferably 2-4 carbons, and containing at least one carbon-carbon double bond.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4- pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkenylene or "alkenylenyl” denotes a divalent group derived from a straight or branched hydrocarbon chain of 2, 3, or 4 carbon atoms and contains at least one carbon-carbon double.
  • alkyl as used herein, means a saturated, straight or branched hydrocarbon chain containing from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2- dimethylpropyl, 1-methylpropyl, 1-ethylpropyl, 1,2,2-trimethylpropyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-oct
  • alkylene or "alkylenyl” means a divalent group derived from a saturated, straight or branched hydrocarbon chain of from 1 to 10 carbon atoms.
  • Ci_6 alkylene means those alkylene or alkylenyl groups having from 1 to 6 carbon atoms.
  • alkylene examples include, but are not limited to, -CH 2 -, -CH(CHs)-, -CH(C 2 H 5 ), -CH(CH(CH 3 )(C 2 H 5 ))-, -C(H)(CH 3 )CH 2 CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, l,l-dimethylprop-2-ynyl, l-propyl-pent-3-ynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • aryl means phenyl, a bicyclic aryl or a tricyclic aryl.
  • the bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl.
  • Non limiting examples of the bicyclic aryl include dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl (including 1,2,3,4- tetrahydronaphthalen-1-yl).
  • the tricyclic aryl is exemplified by a bicyclic aryl fused to a monocyclic cycloalkyl, or a bicyclic aryl fused to a monocyclic cycloalkenyl, or a bicyclic aryl fused to a phenyl.
  • Non limiting examples of tricyclic aryls include anthracene, phenanthrene, dihydroanthracenyl, fluorenyl, 1 ,2-dihydroacenaphthylenyl, and tetrahydrophenanthrenyl.
  • the phenyl, bicyclic and tricyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the phenyl, bicyclic, and tricyclic aryls respectively.
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene or alkylenyl group, as defined herein.
  • Non-limiting examples of arylalkyl include benzyl (phenylmethyl), naphthylmethyl and phenylethyl.
  • cycloalkenyl as used herein, means a monocyclic or bicyclic ring system containing zero heteroatoms in the ring. The monocyclic cycloalkenyl has three-, four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms.
  • the three or four-membered ring systems have one double bond, the five-or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two or three double bonds.
  • Representative examples of monocyclic cycloalkenyls include, but are not limited to, cyclohex-1-en-l-yl, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl, 2,4-cyclohexadien-l-yl and 3- cyclopenten-1-yl.
  • Bicyclic cycloalkenyls are exemplified by a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl.
  • Non limiting examples of bicyclic ring systems include 3a, 4, 5, 6, 7, 7a- hexahydro-lH-indenyl, 4,5,6,7-tetrahydro-3aH-indene, and octahydronaphthalenyl.
  • cycloalkenyl groups are appended to the parent molecular moiety through any substitutable carbon atom within the groups, and can contain one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms, wherein each bridge links two non-adjacent atoms within the groups.
  • cycloalkenylalkyl means a cycloalkenyl group, as defined herein, appended to the parent molecular moiety through an alkylene or alkylenyl group, as defined herein.
  • cycloalkyl as used herein, means a monocyclic, or a bicyclic cycloalkyl, or a spirocyclic cycloalkyl.
  • the monocyclic cycloalkyl is a carbocyclic ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms and zero heteroatoms as ring atoms, and zero double bonds.
  • Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl is exemplified by a monocyclic cycloalkyl fused to a monocyclic cycloalkyl.
  • Non limiting examples of bicyclic cycloalkyls include bicyclo[4.1.0]heptane, bicyclo[6.1.0]nonane, octahydroindene, and decahydronaphthalene.
  • the monocyclic and the bicyclic cycloalkyl groups can contain one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms, wherein each bridge links two non- adjacent atoms within the groups.
  • bridged cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.3.1]nonane, adamantane (tricyclo[3.3.1.1 3 ' 7 ]decane), and noradamantane (octahydro-2,5-methanopentalene).
  • Spirocyclic cycloalkyl is exemplified by a monocyclic or a bicyclic cycloalkyl, wherein two of the substituents on the same carbon atom of the ring, together with the carbon atom, form a A-, 5-, or 6-membered monocyclic cycloalkyl.
  • An example of a spirocyclic cycloalkyl is spiro[2.5]octane.
  • the monocyclic, bicyclic, and spirocyclic cycloalkyl groups are appended to the parent molecular moiety through any substitutable carbon atoms of the groups.
  • cycloalkylalkyl as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkylene or alkylenyl group, as defined herein.
  • halo or halogen as used herein, means -Cl, -Br, -I, or -F.
  • haloalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen.
  • haloalkyl include, but are not limited to, chloromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2- trifluoro-l,l-dimethylethyl, difluoromethyl, 3,3,3-trifluoropropyl, pentafluoroethyl, 2-chloro- 3-fluoropentyl, and 2-iodoethyl.
  • heteroaryl means a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a 5-or 6-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, where the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen atoms can optionally be quarternized.
  • the 5-membered ring contains two double bonds and one, two, three, or four heteroatoms.
  • the 6-membered ring contains three double bonds and one, two, three, or four heteroatoms.
  • Non limiting examples of monocyclic heteroaryl include furanyl (including furan-2-yl, furan-3-yl), imidazolyl (including lH-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl (including l,2,4-oxadiazol-5-yl), oxazolyl (including l,3-oxazol-2- yl), pyridinyl (including pyridin-2-yl, pyridin-4-yl, pyridin-3-yl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl (including thien-2-yl, thien-3-yl), triazolyl, and triazinyl.
  • furanyl including furan-2-yl, furan-3
  • the bicyclic heteroaryl is exemplified by a monocyclic heteroaryl fused to phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle.
  • Non limiting examples of bicyclic heteroaryls include benzofuranyl, benzoxadiazolyl, 1,3- benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothienyl, lH-pyrrolo[2,3-b]pyridinyl (including lH-pyrrolo[2,3-b]pyridin-4-yl), chromenyl, cinnolinyl, furopyridine, indolyl (including lH-indol-3-yl), indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridine and thienopyridinyl.
  • the monocyclic and the bicyclic heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the groups.
  • the nitrogen heteroatoms of the heteroaryl rings can optionally be oxidized, and are contemplated within the scope of the invention.
  • heteroarylalkyl as used herein, means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkylene or an alkylenyl group, as defined herein.
  • heterocycle or “heterocyclic” as used herein, means a monocyclic, bicyclic, or a spirocyclic ring system containing at least one heteroatom selected from nitrogen atom, oxygen atom, and/or sulfur atoms, where the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen atoms can optionally be quarternized.
  • the monocyclic heterocycle is a 3-, 4- 5-, 6-, 7-, or 8-membered monocyclic ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the 3- or 4-membered ring contains 1 heteroatom selected from the group consisting of O, N and S, and optionally one double bond.
  • the 5-membered ring contains zero or one double bond, and one, two or three heteroatoms in the ring selected from the group consisting of O, N and S.
  • the 6-, 7-, or 8-membered ring contains zero, one, or two double bonds, and one, two, or three heteroatoms in the ring selected from the group consisting of O, N and S.
  • Examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3-dioxolanyl, 4,5-dihydroisoxazol-5-yl, 3,4- dihydropyran-6-yl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl (including morpholin-4-yl), oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl (including piperazin-1-y
  • the bicyclic heterocycle is exemplified by a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkylgroup, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl group, or a monocyclic heterocycle fused to a monocyclic heterocycle group.
  • bicyclic heterocycle examples include, but are not limited to, l,3-benzodioxol-4-yl, 1,3- benzodithiolyl, 2,3-dihydro-l,4-benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l- benzothienyl, 2,3-dihydro-lH-indolyl, and 1,2,3,4-tetrahydroquinolinyl.
  • Spirocyclic heterocycle means a monocyclic or bicyclic heterocycle ring wherein two substituents on the same carbon atom, together with the carbon atom, form a A-, 5-, or 6-membered monocyclic cycloalkyl.
  • a spiroheterocycle is 5-oxaspiro[3,4]octane.
  • the heterocycle groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the group.
  • the monocyclic or bicyclic heterocycle groups of the present invention can contain an alkenylene bridge of 2, 3, or 4 carbon atoms, or one or two alkylene bridges of 1, 2, 3, or 4 carbon atoms, wherein each bridge links two non-adjacent carbon atoms within the groups.
  • bridged heterocycles include, but are not limited to, oxaadamantane (2-oxatricyclo[3.3.1.1 3 ' 7 ]decane), octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[ ⁇ ]furan, hexahydro- lH-l,4-methanocyclopenta[c]furan, oxabicyclo [2.2.1] heptane and 2,4- dioxabicyclo[4.2. ljnonane.
  • the nitrogen and sulfur heteroatoms in the heterocycle rings can optionally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl) and the nitrogen atoms can optionally be quarternized.
  • heterocyclealkyl as used herein, means a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkylene or an alkylenyl group, as defined herein.
  • hydroxyalkyl as used herein, means at least one OH group is appended to the parent molecular moiety through an alkylene or an alkylenyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4- hy droxyhepty 1.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • variable groups in compounds of formula (I) are as follows. Such values can be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
  • A is formula (i), (ii), or (iii).
  • Certain embodiments are directed to a group of compounds of formula (I) wherein A is formula (i).
  • compounds within formula (I) include compounds of formula (Ia) and pharmaceutically acceptable salts or solvates thereof:
  • X 1 and X 2 have values as disclosed in the Summary.
  • one aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X 1 is C(O), C(O)N(R 4 ), C(O)O, or S(O) 2 , X 2 is -(CR 611 R 61 VG 1 , -(CR 6a R 6b ) r -X 3 -G 1 , or J A , and X 3 , R 4 , R 6a , R 6b , G 1 , J A , r, and q are as described generally in the Summary and in the embodiments herein.
  • Another aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X 1 is C(O), X 2 is -(CR 6a R 6b ) q -G 1 or J A , and R 6a , R 6b , G 1 , J A , and q are as described generally in the Summary and in the embodiments herein.
  • Another aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X 1 is C(O)N(R 4 ), X 2 is -(CR 6a R 6b ) r -X 3 -G ⁇ or J A , and X 3 , R 4 , R 6a , R 6b , G 1 , J A , r, and q are as described generally in the Summary and in the embodiments herein.
  • Another aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X 1 is C(O)N(R 4 ), X 2 is -(CR 6a R 6b ) q -G 1 , and R 4 , R 6a , R 6b , G 1 , and q are as described generally in the Summary and in the embodiments herein.
  • Another aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X 1 is C(O)N(R 4 ), X 2 is -(CR 6a R 6b ) r -X 3 -G ⁇ and X 3 , R 4 , R 6a , R 6b , G 1 , and r are as described generally in the Summary and in the embodiments herein.
  • X 3 is O.
  • r is 2.
  • Another aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X 1 is C(O)N(R 4 ), X 2 is J A , and R 4 and J A are as described generally in the Summary and in the embodiments herein.
  • Yet another aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X 1 is -C(O)O, X 2 is -(CR 6a R 6b ) q -G 1 , and R 6a , R 6b , G 1 , and q are as described generally in the Summary and in the embodiments herein.
  • a further aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X 1 is S(O) 2 , X 2 is and R 6a , R 6b , G 1 , and q are as described generally in the Summary and in the embodiments herein.
  • Still another aspect is directed to any of the group of compounds of formula (I), (Ia), (Ib), and (Ic) wherein X l -X 2 together is a five membered monocyclic heterocycle or a five membered monocyclic heteroaryl ring, each of which is optionally substituted as described in the Summary and embodiments herein.
  • X*-X 2 together is an optionally substituted five -membered monocyclic heterocycle (e.g. optionally substituted dihydro-l,3-oxazolyl).
  • X*-X 2 together is an optionally substituted f ⁇ ve-membered monocyclic heteroaryl ring (for example, 1,2,4-oxadiazolyl or oxazolyl, each of which is optionally substituted).
  • the five membered monocyclic heterocycle or five membered monocyclic heteroaryl ring aryl is substituted with one G 2 such as, but not limited to, aryl (for example, phenyl) and heteroaryl (for example, pyridinyl), each of which is independently further substituted as described in the Summary; and optionally further substituted with one other R 7c group such as, for example, alkyl, halogen, or haloalkyl.
  • X*-X 2 together is (iv), (v), or (vi)
  • R 4 for example, includes hydrogen and alkyl (e.g. methyl). In certain embodiments, R 4 is hydrogen.
  • R 6a and R 6b have values as described in the Summary and in embodiments herein.
  • R 6a and R 6b at each occurrence, are each independently hydrogen, alkyl (e.g. methyl), optionally substituted aryl (e.g. optionally substituted phenyl), arylalkyl (such as, but not limited to, benzyl), or alkyl substituted with one -OR U group wherein R u is as described in the Summary and embodiments herein.
  • R u is hydrogen.
  • R 6a and R 6b at each occurrence, are each independently hydrogen, alkyl (e.g. methyl), unsubstituted or substituted phenyl, or -CH 2 OH.
  • G 1 include cycloalkyl (e.g. cyclohexyl), cycloalkenyl (e.g. cyclohexenyl), heteroaryl (e.g. thienyl, furanyl, pyridinyl, imidazolyl, oxazolyl, indolyl), heterocycle (e.g. tetrahydrothienyl, tetrahydrofuranyl, dioxidotetrahydrothienyl), and aryl (e.g. phenyl, naphthyl).
  • G 1 is aryl (e.g. phenyl, naphthyl).
  • Each G 1 is independently unsubstituted or substituted with 1, 2, 3, 4, 5 substituents as represented by R 7b .
  • R 7b include, but are not limited to, alkyl (e.g. methyl), halogen (e.g. Br, F, Cl, I), haloalkyl (e.g. trifiuoroalkyl), OR 7ab , SR 7ab , N(R b )(R 7ab ), C(O)NR 7ab R b , and -O(CR ax R bx ),O-, wherein R b , R 7ab , R ax , R bx , and t are as described in the Summary and in the embodiments herein.
  • each occurrence of R 7ab is independently hydrogen, alkyl (e.g. methyl, ethyl, propyl), haloalkyl (e.g. trifluoromethyl), or -(Ci_6 alkylene)-G 2 wherein G 2 is a heterocycle such as, but not limited to, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, and tetrahydrofuranyl; each of which is optionally substituted as described in the Summary.
  • R 7b is alkyl (e.g. methyl, ethyl), halogen (e.g.
  • J A has values as described generally in the Summary and in embodiments herein.
  • J A is a monocyclic cycloalkyl optionally substituted with 1, 2, 3, 4, 5, or 6 substituents as represented by R 7JA ; two R 7JA on the adjacent carbon atoms of J A , together with the carbon atoms to which they are attached, optionally form a benzo, a monocyclic heterocycle, a monocyclic cycloalkyl, or a monocyclic cycloalkenyl ring wherein each of the rings is independently unsubstituted or substituted with 1, 2, or 3 substituents as represented by R 7b .
  • J A is a monocyclic cyclohexyl fused with a benzo group.
  • J A is an optionally substituted monocyclic heterocycle ring.
  • the optionally substituted monocyclic heterocycle ring include piperazinyl, pyrrolidinyl, piperidinyl, morpholinyl, each of which is optionally substituted as described in the Summary and embodiments herein.
  • the optional substituents of J A include, but are not limited to, alkyl (e.g. methyl, ethyl, propyl, isopropyl) and G 2 (e.g. optionally substituted aryl such as, but not limited to, optionally substituted phenyl).
  • m, n, and p have values as described generally in the Summary and embodiments herein. In certain embodiments, m, n, and p are 0. In yet other embodiments, m is 1, and n and p are as described in the Summary.
  • R 1 , R 2 and R 3 are as described generally in the Summary and embodiments herein.
  • R 1 is alkyl such as, but not limited to, methyl.
  • R 2 for example, is aryl (e.g. phenyl) or arylalkyl (e.g. benzyl).
  • R 3 for example, is halogen (e.g. Cl, Br) or NR a R b .
  • Exemplary compounds include, but are not limited to:
  • a bond drawn from a substituent to the center of one ring within a bicyclic ring system as shown in formula (Ia), (Ib), (Ic), (i), (ii), and (iii), represents substitution of the substituents at any substitutable carbon atoms within the bicyclic ring system, unless stated otherwise.
  • Individual stereoisomers are contemplated in the present application.
  • Individual stereoisomers can be prepared synthetically from commercially available chiral reagents or by stereoselective or stereospecific synthetic techniques.
  • the single enantiomers or diastereomers can be obtained from the preparation of racemic mixtures followed by resolution of the individual stereoisomer using methods that are known to those of ordinary skill in the art.
  • resolution examples are, for example, (i) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, followed by liberation of the optically pure product; or (ii) separation of the mixture of enantiomers or diastereomers on chiral chromatographic columns.
  • Geometric isomers can also exist in the present compounds. Various geometric isomers and mixtures thereof resulting from the disposition of substituents around a carbon- carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle group are also contemplated. Substituents around a carbon-carbon double bond or a carbon- nitrogen bond are designated as being of Z or E configuration and substituents around a cycloalkyl or a heterocycle are designated as being of cis or trans configuration.
  • the individual geometric isomers can be prepared selectively by methods known to the skilled artisan, or mixtures of the isomers can be separated by standard chromatographic or crystallization techniques.
  • Isotopes can be radioactive or nonradioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 32 P,
  • the isotope-labeled compounds contain deuterium ( 2 H), tritium ( 3 H) or 14 C isotopes.
  • Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope- labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope- labeled reagent for a non-labeled reagent.
  • compounds can be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as D 2 SO 4 ZD 2 O.
  • the isotope-labeled compounds of the invention can be used as standards to determine the effectiveness of ROCK inhibitors in binding assays.
  • Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)).
  • non-radio active isotope containing drugs such as deuterated drugs called “heavy drugs”
  • Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment.
  • Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.
  • Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom can be stronger than the same bond between the light isotope and that atom.
  • Sciatic Nerve Ligation Model of Neuropathic Pain As described in details by Bennett and Xie (Bennett G. J.; and Xie Y-K., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, 1988, 33, 87-107), a 1.5 cm incision was made 0.5cm below the pelvis and the biceps femoris of anesthetized rats, and the gluteous superf ⁇ cialis (right side) were separated. The sciatic nerve was exposed, isolated, and four loose ligatures (5-0 chromic catgut) with 1 mm spacing were placed around it.
  • mice were allowed to recover and then placed in a cage with soft bedding for 14 days before behavioral testing for mechanical allodynia as described above.
  • animals were also tested for cold allodynia by dipping their hind paw in a cold-water bath (4.5 0 C) and determining the paw withdrawal latency.
  • ROCK antagonistic activity Because of their profile, the compounds can be used for treating diseases which respond to the influencing of ROCK activity, i.e. they are effective for treating those medical disorders or diseases in which exerting an influence on (modulating) the ROCK activity leads to an improvement in the clinical picture or to the disease being cured. Examples of these diseases are given above.
  • cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, chronic renal failure, cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension, and ocular hypertension; cancer and tumor metastasis, asthma; male erectile dysfunctions; female sexual dysfunctions; over-active bladder syndrome; preterm labor; ischemia reperfusion; myocardial infarction; restenosis; atherosclerosis; graft failure; CNS disorders, such as acute neuronal injury, e.g.
  • disorders are cancer, pain (e.g. inflammatory pain, neuropath tic pain, nociceptive pain, cancer pain, and the like), asthma, cognitive dysfunctions, in particular vascular dementia and Alzheimer's disease, multiple sclerosis, rheumatoid arthritis and spinal cord injuries.
  • a treatment also includes a preventive treatment (prophylaxis), in particular as relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
  • the treatment can be orientated symptomatically, for example as the suppression of symptoms. It can be effected over a short period, be orientated over the medium term or can be a long-term treatment, for example within the context of a maintenance therapy.
  • the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other active compounds or active compound- containing preparations.
  • the use according to the invention of the described compounds involves a method.
  • an effective quantity of one or more compounds is administered to the individual to be treated, preferably a mammal, in particular a human being, productive animal or domestic animal.
  • a mammal in particular a human being, productive animal or domestic animal.
  • Present compounds can also be administered as a pharmaceutical composition including therapeutically effective amounts of the compounds of interest in combination with one or more pharmaceutically acceptable carriers.
  • therapeutically effective amount means sufficient amount of the compounds to achieve the desired therapeutic response for a particular patient, compositions and mode of administration, at a reasonable benefit/risk ratio applicable to any medical treatment. It can be understood, however, that the total daily usage of the compounds and compositions can be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient can depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds administered to a human or lower animal can range from about 0.003 to about 30 mg/kg/day.
  • more preferable doses can be in the range of from about 0.01 to about 10 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. e.
  • Pharmaceutical Compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • compositions capable of treating protein kinases associated conditions, in particular, Rho kinase (ROCK) mediated conditions, as described above.
  • Pharmaceutical compositions including compounds of interest, or solvates or salts thereof can be formulated by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutically acceptable additives of a type appropriate to the mode of administration (e.g. excipients, binders, preservatives, stabilizers, flavors, etc) according to techniques such as those well known in the art of pharmaceutical formulations.
  • the compounds described herein can be administered by any means suitable for the condition to be treated, which can depend on the need of site-specific treatment or quantity of drug to be delivered.
  • compositions can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and
  • compositions of this invention for parenteral injection include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound can be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h)
  • Solid compositions of a similar type can also be employed as fillers in soft and hard- filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms can contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsif ⁇ ers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsif ⁇ ers such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
  • compositions for rectal or vaginal administration include suppositories which can be prepared by mixing the compounds of interest with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to the compounds of interest, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • Dosage forms for topical administration of the compounds include powders, sprays, ointments and inhalants.
  • the active compound(s) can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the compounds provided herein can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecan
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • prodrug or “prodrug”as used herein, represents those prodrugs of the compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • prodrug or “prodrug”as used herein, represents those prodrugs of the compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • the present application contemplates compounds formed by synthetic means or formed by in vivo biotransformation of a prodrug.
  • This invention is intended to encompass compounds of the invention when prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • the compounds provided herein can be prepared by a variety of processes well known for the preparation of compounds of this class.
  • compounds of formula (I) wherein the groups A, X 1 , X 2 , m, n, p, R 1 , R 2 , R 3 , and R 4 have the meanings as set forth in the summary section unless otherwise noted, can be generally prepared as shown in Schemes 1-3.
  • HPLC high performance liquid chromatography or high pressure liquid chromatography
  • dppf for [l,l'-bis(diphenylphosphino)ferrocene
  • DME dimethoxy ethane
  • DMSO dimethylsulfoxide
  • triflate for trifluoromethylsulfonate
  • OMs or mesylate for methanesulfonate
  • tBu for tert-butyl
  • OTs or tosylate for p-toluenesulfonate.
  • Compounds of formula (1) can be treated with isocyanates of formula X 2 NCO or reagents of formula (2) using reaction conditions that are known in the art to provide compounds of formula (3) wherein R 4 is hydrogen.
  • the reaction can be conducted at ambient temperature in the presence of a base such as triethylamine.
  • Compounds of formula (3) can also be prepared by treating (1) with an appropriate amine of formula X 2 N(H)(R 4 ) in the presence of triphosgene, 4-nitrophenyl carbonochloridate, or bis(2,5-dioxopyrrolidin-l-yl)carbonate, and a base such as triethylamine to provide (3). While subjected to conditions known to those skilled in the art, compounds of formula (1) can be treated with (2) to provide (3).
  • Compounds of formula (4) can be obtained by treating compounds of formula (1) with chloroformates of formula ClC(O)OX 2 in the presence of a base such as triethylamine.
  • Compounds of formula (5) can be obtained by treating compounds of formula (1) with sulfonyl chlorides of formula X 2 S(O) 2 Cl in the presence of a base such as triethylamine.
  • Removal of the tert-butoxy carbonyl group on the tetrahydropyridine ring can be accomplished by treatment with an acid.
  • R 102 is toluenesulfonyl or benzenesulfonyl can be removed by treatment with an hydroxide such as sodium hydroxide. Treatment with tetrabutylammonium fluoride would remove the triisopropylsilyl protecting group.
  • reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
  • an optically active form of a compound of the invention can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
  • an optically active starting material prepared, for example, by asymmetric induction of a suitable reaction step
  • resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
  • a pure geometric isomer of a compound of the invention when required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
  • Examples can be used for illustrative purposes and should not be deemed to narrow the scope of the invention.
  • Examples Products or intermediates that were purified by preparative HPLC were conducted on a Phenomenex Luna C 8(2) 5 um IOOA AXIA column (30mm x 75mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 70mL/min (0-0.5 min 10% A, 0.5-12.0 min linear gradient 10-95% A, 12.0-15.0 min 95% A, 15.0-17.0 min linear gradient 95-10% A). Samples were injected in 2.5mL dimethyl sullfoxide methanol (1 :1).
  • a custom purification system was used, consisting of the following modules: Waters LC4000 preparative pump; Waters 996 diode-array detector; Waters 717+ autosampler; Waters SAT/IN module, Alltech Varex III evaporative light- scattering detector; Gilson 506C interface box; and two Gilson FC204 fraction collectors.
  • the system was controlled using Waters Millennium32 software, automated using an Abbott developed Visual Basic application for fraction collector control and fraction tracking.
  • N-benzyl-4-(lH-pyrrolor2,3-blpyridin-3-yl)-3,6-dihydropyridine-l(2H)-carboxamide A mixture of 3-(l,2,3,6-tetrahydropyridin-4-yl)-lH-pyrrolo[2,3-b]pyridine (80 mg, 0.40 mmol), triethylamine (0.056 mL, 0.40 mmol), and (isocyanatomethyl)benzene (0.049 mL, 0.40 mmol) in N,N-dimethylformamide (1.2 mL) was stirred for 90 min at room temperature, diluted with ethyl acetate, washed with water and brine, dried (Na 2 SO 4 ), concentrated, filtered, and chromatographed (3 to 5% methanol/dichloromethane) to give the title compound as a yellow solid (82 mg, 0.25 mmol).
  • Example 6 3- ⁇ l-r(3-phenylmorpholin-4-yl)carbonyll-l,2,3,6-tetrahvdropyridin-4-vU-lH-pyrrolor2,3- blpyridine
  • the title compound was prepared using the procedure in Example IB replacing the product from Example IA with 3-phenylmorpholine hydrochloride.
  • Example 7 3- ⁇ 1 -r(4-methyl-2-phenylpiperazin- 1 -vDcarbonyll- 1 ,2,3 ,6-tetrahydropyridin-4-vU -IH- pyrrolor2,3-blpyridine
  • the title compound was prepared using the procedure in Example IB, replacing the product from Example IA with l-methyl-3-phenylpiperazine.
  • Example 11 N-(2-phenylethyl)-4-(lH-pyrrolor23-b1pyridin-3-yl)-3.6-dihvdropyridine-
  • Example 11 replacing (2-isocyanatoethyl)benzene with 2,4-dichloro-l- (isocyanatomethyl)benzene.
  • Example 11 replacing (2-isocyanatoethyl)benzene with l-(isocyanatomethyl)-4- methoxybenzene.
  • Example 11 replacing (2-isocyanatoethyl)benzene with l-(2-isocyanatoethyl)-3,5- dimethoxybenzene.
  • Example 29 N-[2-(2,3-
  • the trifluoroacetic acid salt of the title compound was prepared using the procedure in Example 11 replacing (2-isocyanatoethyl)benzene with l-(2-isocyanatoethyl)-2,3- dimethoxybenzene.
  • Example 11 replacing (2-isocyanatoethyl)benzene with 4-(2-isocyanatoethyl)- 1,2- dimethoxybenzene.
  • Example 11 replacing (2-isocyanatoethyl)benzene with l-chloro-4-(2- isocyanatoethyl)benzene.
  • Example 44 N-(cyclohexylmethyl)-4-(lH-pyrrolo[2,3-blpyridin-3-yl)-3
  • Example 11 replacing (2-isocyanatoethyl)benzene with (4-isocyanatobutyl)benzene.
  • Example 51 3 -(I - ⁇ 4-methyl-5-[3-(trifluoromethyl)phenyll- 1 ,3-oxazol-2-yl
  • pyridine Example 51 A
  • Example IB The title compound was prepared using the procedure in Example IB replacing the product from Example IA with (R)-N-methyl-l-phenylethanamine.
  • the mixture was passed through a SiliCycle SiliaBond Carbonate solid phase extraction column with methanol, concentrated, and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um IOOA AXIA column (30mm x 75mm) using a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 50mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A) to provide the trifluoroacetic acid salt of the title compound.
  • A acetonitrile
  • B trifluoroacetic acid in water
  • Example 60 4-( 1 H-pyrrolo [2 ,3 -blpyridin-3 -yl)-N- r4-(trifluoromethoxy)benzyll -3 ,6-dihydropyridine-
  • Example 58 replacing (3-fluoro-5-(trifluoromethyl)phenyl)methanamine with (4- (trifluoromethoxy)phenyl)methanamine.
  • the trifluoroacetic acid salt of the title compound was prepared using the procedure in Example 58 replacing (3-fluoro-5-(trifluoromethyl)phenyl)methanamine with 1,2,3,4- tetrahydronaphthalen-1 -amine.
  • Example 58 replacing (3-fluoro-5-(trifluoromethyl)phenyl)methanamine with 1,2- diphenylethanamine.
  • 1 H NMR 500 MHz, DMSO-d 6 /Deuterium Oxide
  • Example 58 replacing (3-fluoro-5-(trifluoromethyl)phenyl)methanamine with (2,3- dichlorophenyl)methanamine.
  • Example 58 replacing (3-fluoro-5-(trifluoromethyl)phenyl)methanamine with 3,3- diphenylpropan-1 -amine.
  • Example 58 replacing (3-fluoro-5-(trifluoromethyl)phenyl)methanamine with 2-(lH-indol-3- yl)ethanamine.
  • Example 77 The title compound was prepared using the procedure in Example IB replacing the product from Example IA with (R)-l-(3-methoxyphenyl)ethanamine.
  • Example 77A The product of Example 77A was stirred in 10% CF3CO2H in methanol (3 mL) for 1 h at room temperature, concentrated, diluted with sat NaHCO 3 , extracted with dichloromethane, and dried (Na 2 SO 4 ). The aqueous and organic layers were combined, concentrated, triturated with 20% isopropanol/CHCl3, and concentrated to give 280 mg of a tan gum.
  • Step B A mixture of (R)-l-(3-methoxyphenyl)ethanamine (71.5 mg, 0.473 mmol), triethylamine (0.081 mL, 0.58 mmol), and triphosgene (48.5 mg, 0.163 mmol) in dichloromethane (1.5 mL) was stirred 2 h at room temperature, and added to a mixture of the product from Step A, triethylamine (0.08 mL, 0.6 mmol), and N,N-dimethylformamide (2 mL).
  • Example 77 The title compound was prepared using the procedures described for the preparation of Example 77, replacing 4-bromo-lH-pyrrolo[2,3-b]pyridine used in Example 77A with 5- bromo-lH-pyrrolo[2,3-b]pyridine.
  • 1 H NMR 300 MHz, DMSO-J 6 ) ⁇ ppm 11.59 (bs, IH),

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Abstract

L'invention concerne des composés de formule (I) ou leurs sels pharmaceutiquement acceptables, dans lesquels A, X1, X2, R1, R2, R3, m, n, et p sont définis dans la description. L'invention concerne également des compositions contenant les composés qui peuvent être utiles pour inhiber la Rho kinase (ROCK) et des procédés pour utiliser les compositions.
PCT/US2009/052617 2008-08-05 2009-08-03 Composés utiles comme inhibiteurs de protéine kinases WO2010017150A1 (fr)

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MX2011001370A MX2011001370A (es) 2008-08-05 2009-08-03 Compuestos utiles como inhibidores de cinasas de proteina.
CN2009801395015A CN102170883A (zh) 2008-08-05 2009-08-03 可用作蛋白激酶抑制剂的化合物
JP2011522150A JP2011530518A (ja) 2008-08-05 2009-08-03 タンパク質キナーゼの阻害剤として有用な化合物
CA2731095A CA2731095A1 (fr) 2008-08-05 2009-08-03 Composes utiles comme inhibiteurs de proteine kinases
EP09805407A EP2323659A4 (fr) 2008-08-05 2009-08-03 Composés utiles comme inhibiteurs de protéine kinases

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WO2013078413A1 (fr) * 2011-11-22 2013-05-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Modulateurs du stockage lipidique
US9617260B2 (en) 2013-04-02 2017-04-11 Hoffmann-La Roche Inc. Inhibitors of bruton's tyrosine kinase
US11198680B2 (en) 2016-12-21 2021-12-14 BioAxone BioSciences, Inc. Rho kinase inhibitor BA-1049 (R) and active metabolites thereof
US11701366B2 (en) 2015-01-26 2023-07-18 BioAxone BioSciences, Inc. Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors

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FR3000493A1 (fr) * 2012-12-28 2014-07-04 Oribase Pharma Nouveaux inhibiteurs de proteines kinases
JP6559785B2 (ja) 2014-12-15 2019-08-14 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン Ｅｇｆｒ及びｐｉ３ｋの小分子阻害剤
JP7117306B2 (ja) * 2016-12-21 2022-08-12 バイオアクソン バイオサイエンシーズ インコーポレイテッド Ｒｈｏキナーゼ阻害剤ＢＡ‐１０４９（Ｒ）及びその活性代謝物
US11685733B2 (en) 2018-01-19 2023-06-27 Children's Medical Center Corporation Compounds for treating Rac-GTPase mediated disorder
EP4267554A1 (fr) 2020-12-22 2023-11-01 Mekanistic Therapeutics LLC Composés d'hétéroaryle d'aminobenzyle substitués utilisés en tant qu'inhibiteurs d'egfr et/ou de pi3k
CN113171363A (zh) * 2021-05-06 2021-07-27 北京工业大学 Y-39983 HCl在制备抗病毒药物中的应用
CN113461683B (zh) * 2021-07-07 2022-11-22 青岛科技大学 一种7-氮杂吲哚类杂环化合物及其制备方法和应用

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US9617260B2 (en) 2013-04-02 2017-04-11 Hoffmann-La Roche Inc. Inhibitors of bruton's tyrosine kinase
US11701366B2 (en) 2015-01-26 2023-07-18 BioAxone BioSciences, Inc. Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors
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US11814361B2 (en) 2016-12-21 2023-11-14 BioAxone BioSciences, Inc. Rho kinase inhibitor BA-1049 (R) and active metabolites thereof

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CN102170883A (zh) 2011-08-31
JP2011530518A (ja) 2011-12-22
MX2011001370A (es) 2011-03-15

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